An alternative convenient synthesis of piperidazine-3-carboxylic acid derivatives

Article abstract of DOI:10.1248/cpb.57.49

The short-step synthesis of the unsubstituted, 5-hydroxy- and 5-chloropiperidazine-3-carboxylic acids using an aza Diels-Alder reaction between the 1,3-diene and azodicarboxylate was described. This synthetic methodology could be used for the preparation

Full text of DOI:10.1248/cpb.57.49

January 2009
Chem. Pharm. Bull. 57(1) 49—54 (2009)
49
An Alternative Convenient Synthesis of Piperidazine-3-carboxylic Acid
Derivatives
*
Mamoru KANAME, Masae YAMADA, Shigeyuki YOSHIFUJI, and Haruki SASHIDA
Faculty of Pharmaceutical Sciences, Hokuriku University; Kanagawa-machi, Kanazawa 920–1181, Japan.
Received August 22, 2008; accepted October 17, 2008; published online October 20, 2008
The short-step synthesis of the unsubstituted, 5-hydroxy- and 5-chloropiperidazine-3-carboxylic acids using
an aza Diels–Alder reaction between the 1,3-diene and azodicarboxylate was described. This synthetic methodol-
ogy could be used for the preparation of the optically active piperazic acid in a 35% overall yield.
Key words aza Diels–Alder reaction; piperidazine-3-carboxylic acid; azodicarboxylate; piperazic acid
Hexahydropyridazine-3-carboxylic acid (piperazic acid, of the DA adducts into the dimethylphosphono group by
Piz) is a novel cyclic a-hydrazino acid, and a subunit often treatment with trimethylphosphite in the presence of a Lewis
found in cyclic depsipeptides. Both of its enantiomeric forms acid.18—20) The treatment of the methoxy DA adduct (7) with
have been encountered in many pharmacologically active trimethylsilyl cyanide (TMSCN) in the presence of BF3·OEt2
molecules that include the azinothricin family of antitumor as a Lewis acid at ꢀ40 °C in dry CH2Cl2 gave the 3-cyano-
antibiotics,1) verucopeptin,2) the aurantimycins,3) the C5a an- 1,2,3,6-tetrahydropyridazine (6) in 94% yield via the acylim-
tagonist L-156,602,4) the immunosuppressant IC101,5) the inium cation intermediate. When TiCl4 was used in this cya-
oxytocin antagonist L-156,373,6) and the matylastantin type- nation reaction, the 3-cyanopyridazine (6) was also produced
IV collagenase inhibitors.7—9) There are several reports10—13) in almost a similar yield. In addition, the one-pot preparation
about the synthesis of the racemic Piz. However, these re- of the 3-cyanopyridazine (6) was established. The reaction
ports have indicated some obstacles still to be overcome; the of 1-methoxy-1,3-butadiene (3) with di-tert-butyl azodicar-
aza Diels–Alder (DA) reaction for the construction of the boxylate (4) in dry CH2Cl2 at room temperature, followed by
pyridazine framework has a low yield, and the N-deprotec- the addition of TMSCN and BF3·OEt2 at ꢀ40 °C directly af-
tion was done under strict basic conditions. Recently, Hale forded the desired 3-cyanopyridazine (6) in 91% yield. The
and co-workers14,15) described the enantioselective synthesis DA reaction using 1-trimethylsilyloxy-1,3-diene (8) and
of the (3R)- and (3S)-piperazic acids by the electrophilic hy- azodicarboxylate (4) under similar conditions produced the 6
drazination of a chiral oxazorizinone derivative. More re- in 80% yield (Chart 2).
cently, Hamada and co-workers reported two synthetic meth-
The catalytic hydrogenation of the olefin moiety in 6 using
ods for optically active piperazic acids by the use of a pro- Pd–C or PtO2 in EtOH was examined. The results of the hy-
line-catalyzed asymmetric a-hydrazination16) and the tita- drogenation are summarized in Chart 3 and Table 1. The
nium tetrachloride-mediated aza DA reaction.17) Although 10% Pd–C hydrogenation of 6 at the 1 or 3 atom of H2 gave
(3S,5S)-5-HO-Piz was also prepared, the methodology for the desired 3-cyanohexahydropyridazine (9) and the amino-
the preparation of these compounds requires multiple steps, methyl derivative (11), which was isolated as the N-Boc de-
which is not practical. In this report, we describe three new rivative 12 by the treatment with Boc2O (entries 1—3). In the
findings for the synthesis of the Piz derivatives; (1) the short- case of using PtO2, 3-cyano-1,2,5,6-tetrahydropyridazine
step convenient synthesis of Piz, (2) the practical preparation (10) was produced as the major product (entry 5). Fortu-
of the 5-hydroxy and 5-chloro Piz, and (3) the (R)- and (S)- nately, the PtO2 hydrogenation of 6 at the 1 atom of H2 in
Piz enantioselective synthesis.
EtOH with 2 drops of a 70% HClO4 solution as an additive
Results and Discussion
Convenient Synthesis of Piperidazine-3-carboxylic
Acids In order to prepare the pyridazine-3-carboxylic acid
derivative, the DA reaction using the 1,3-diene and azodicar-
boxylate was carried out. The hetero DA reaction between
the di-tert-butyl azodicarboxylate (4) and the 1,3-dienes (1,
2), which have an electron withdrawing group, such as a
methoxycarbonyl or cyano group, produced the 1,2-di-tert-
butyl 1,2,3,6-tetrahydropyridazine-1,2-carboxylate adducts
(5, 6) in 47 and 40% yields, respectively. In contrast, a simi-
lar reaction of the azodicarboxylate (4) with methoxy-1,3-
diene (3), which has an electron donating group, gave the 3-
methoxypyridazine (7) in almost quantitative yield (Chart
1).18) Therefore, we examined the transformation of the
methoxy group in the 3-methoxypyridazine (7) into the
cyano group for preparation of the subtitled compounds. We
have described the smooth conversion of the methoxy group
Chart 1
Chart 2
∗ To whom correspondence should be addressed. e-mail: h-sashida@hokuriku-u.ac.jp
© 2009 Pharmaceutical Society of Japan

50
Vol. 57, No. 1
Chart 3
Table 1. Catalytic Hydrogenation of 6
Reaction conditions
Product yield (%)
Entry
Pressure
(atm)
Time
(h)
Catalyst
Additive
9
10
12
1
2
3
4
5
6
10% Pd–Ca)
10% Pd–Ca)
10% Pd–Cb)
10% Pd–Cb)
PtO2
—
—
—
HClO4
—
HClO4
3
1
1
1
1
1
2
10
3
1
5
54
64
54
59
17
95
—
—
—
—
77
—
27
22
37
17
—
—
PtO2
1
a) 40 mg, b) 420 mg.
duction decreased. The lithium tri-tert-butoxyaluminumhy-
dride reduction of 17 in tetrahydrofuran (THF) at ꢀ20 °C
produced 18 and 19 in almost a similar ratio and 96% yield.
The hydride reduction seemed to occur by the apparent less
hindered attack on the carbonyl group at the C-5 position of
the most stable quasi-chair conformer of the 5-oxohexahy-
dropyridazine ring 17A, which is more favored than 17B due
Chart 4
afforded the desired 3-cyanohexahydropyridazine (9) in 95% to the steric hindrance of the two Boc groups as shown in
yield as the sole product (entry 6). 9 was obtained in 59% Chart 6. Therefore, the stereochemistry of the cyano and hy-
yield together with 12 in 17% yield using a 10% Pd–C cata- droxy groups in the major isomer seems to be cis, although
lyst under similar conditions (entry 4).
specific evidence for this isomer is not available. This stereo-
In order to convert into the desired Piz, the deprotection of chemistry was finally determined by conversion into the 5-
the N-Boc group and hydrolysis of the 3-cyanohexahydropy- hydroxy Piz from the major cis-isomer.
ridazine (9) were carried out (Chart 4). Refluxing 9 in 6 M
Both isomers 18 and 19 were heated in a refluxing mixed
HCl for 24 h, followed by the treatment with an ion-exchange solution of 6 M HCl and AcOH for 24 h to afford the corre-
resin (Dowex 1ꢁ4), and then the addition of trifluoroacetic sponding acids 20 and 21, which were immediately con-
acid (TFA) furnished the desired Piz 13 in 93% yield. The verted into the N-dinitrophenyl (DNP) derivatives 22 and 23
1H-NMR spectral data of 13 was in good agreement with that by the reaction with 1-fluoro-2,4-dinitrobenzene in 92 and
1
of the known optically active compound in the literature.16)
72% yields, respectively. The H-NMR spectral data of the
Synthesis of 5-Substituted Piperidazine-3-carboxylic cis-DNP derivatives 22 was in complete agreement with that
Acids We next planned the synthesis of the 5-substituted of (3S,5S)-1-DNP-5-OH-Piz in the literature. 21)
piperidazine-3-carboxylic acids through the aza-DA reaction
Both of the 5-hydroxy enantiomers 18 and 19 were chlori-
between the Danishefsky reagent (1-methoxy-3-trimethylsi- nated using the Mitsunobu22) reaction, which is well known
lyloxy-1,3-butadiene) and azodicarboxylate. The aza-DA re- as the stereospecific inversion of the hydroxy group into the
action of 3-trimethylsilyloxy-1,3-butadiene (14) with 4 in dry chloro group. The cis-5-chlorohexahydropyridazine (25) was
CH2Cl2, followed by the treatment with TMSCN in the pres- produced by the reaction of 19 with PPh3 and CCl4 in THF in
ence of BF3·OEt2 as a Lewis acid at ꢀ40 °C, and then 60% yield. Similarly, the trans-derivative 24 was obtained
NaHCO3 hydrolysis, successfully gave the 3-cyano-5-oxo- from the corresponding 18 in 70% yield, and then hydrolyzed
hexahydropyridazine (17) in 94% yield in one-pot via the in- with 6 M HCl to give the pyridazinecarboxylic acid (26),
termediates 15 and 16. The NaBH4 reduction of 17 in EtOH which was transformed into the DNP derivative 27 without
1
at ꢀ20 °C gave a mixture of the 5-hydroxy derivatives cis-18 isolation in 81% yield. The H-NMR spectral data of the
and trans-19 in the ratio of 72 : 28 with a 95% yield, which trans-DNP derivatives 27 was in accord with that reported
could be easily separated by silica gel column chromatogra- for the optically active compound.
phy. This NaBH4 reduction quickly proceeded at room tem-
Optically Active Piperidazine-3-carboxylic Acids Fi-
perature giving 18 and 19, however, the selectivity of the re- nally, we achieved the asymmetric synthesis of both enan-

January 2009
51
Chart 5
ꢃ11.1 (cꢂ0.98, MeOH)}.
Conclusion
In this study, we established the short-step preparation of
the racemic unsubstituted, 5-hydroxy and 5-chloro Piz, and
succeeded in the preparation of both enantiomers of the opti-
cally active Piz in three steps with 35% overall yields
through the DA reaction and cyanation.
Experimental
Melting points were measured on a Yanagimoto micro melting point hot
stage apparatus and are uncorrected. IR spectra were determined with a
Horiba FT-720 spectrometer. Mass spectra (MS) and HR-MS were recorded
on a JEOL JMS-DX300 instrument. NMR spectra were determined with a
JEOL EX-90A (90 MHz) or a JEOL JNM-GSX 400 (400 MHz) spectrome-
ter in CDCl3, DMSO-d6 or D2O using tetramethylsilane as internal standard
and J values are given in Hz. Microanalyses were performed in the Microan-
alytical Laboratory in this Faculty.
Chart 6
tiomers of the Piz from the 1,3-dienes and optically active
azodicarboxylate as the starting material by the previously
described method. While several reports14—17,23,24) on the syn-
theses of the optically active Piz are known, these prepara-
tions remain much less explored regarding the synthetic steps
and the yields for the preparation of both enantiomers. The
treatment of 1-methoxy-1,3-diene (3) with di-(ꢀ)-menthyl
azodicarboxylate (28) in dry CH2Cl2 at room temperature,
followed by the addition of TMSCN in the presence of
BF3·OEt2 or TiCl4 at ꢀ40 °C gave the desired 3-cyano-
1,2,3,6-tetrahydropyridazine (29) as a mixture of the two di-
astereomers in excellent yields, which were not able to be
separated. The PtO2 catalytic hydrogenation of the olefin
moiety in 29 in the presence of 70% HClO4 gave the (R)-
Starting 2,4-Dienes and Azodicarboxylate Methy pentadienate (1),25)
penta-2,4-dienenitrile (2)26) and di-tert-butyl azodicarboxylate (4)27) were
prepared by the reported methods.
General Procedure for the Diels–Alder Reaction of 1,3-Diene with
Azocarboxylate 1,3-Butadiene (1—3, 10 mmol) was added to a solution
of di-tert-butyl azodicarboxylate (4, 2.30 g, 10 mmol) in an appropriate sol-
vent (10 ml). The mixture was refluxed or stirred for 2—72 h until disap-
pearance of the starting material, and then evaporated in vacuo. The result-
ing residue was purified by silica gel chromatography to give 5—7.
Di-tert-butyl 3-Methyl 1,2,3,6-Tetrahydropyridazine-1,2,3-tricarboxy-
late (5) The reaction was carried out in refluxing benzene for 72 h. Color-
less prisms, mp 100—103 °C (from hexane). MS m/z 342 (Mꢃ). IR (KBr)
cmꢀ1: 1759, 1697 (CꢂO). 1H-NMR (CDCl3) d: 1.48 (18H, s, t-Buꢁ2), 3.74
(3H, s, 3-COOMe), 3.56—3.92 and 4.24—4.52 (each 1H, m, 6-H2), 5.07—
form 30 and (S)-form 31 in 42 and 40% yields, respectively. 5.40 (1H, m, 3-H), 5.87—6.01 (2H, m, 4-, 5-H). 13C-NMR (CDCl3) d: 28.21
(q), 28.24 (q), 41.5 (t), 52.3 (q), 55.5 (d), 80.7 (s), 82.0 (s), 122.3 (d), 125.5
The diastereomers 30 and 31 could be easily separated by sil-
ica gel column chromatography. Transformation from the
(S)-form 31 into the (R)-form 30 under basic conditions was
(d), 153.9 (s), 154.4 (s), 169.1 (s). Anal. Calcd for C16H26N2O6: C, 56.13; H,
7.65; N, 8.18. Found: C, 56.12; H, 7.48; N, 8.26.
Di-tert-butyl 3-Cyano-1,2,3,6-tetrahydropyridazine-1,2-dicarboxylate
found. The catalytic hydrogenation of 29 gave a mixture of
30 and 31, epimerization of which with 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) in refluxing EtOH for 2 h finally
afforded the mixture of 30 and 31 in 50 and 11% isolated
yields, respectively. The hydrolysis of the (R)-form 30 with
6 M HCl, followed by purification using an ion-exchange
resin (Dowex 1ꢁ4), and then the addition of TFA gave the
optically pure Piz 32 {mp 145—147 °C, [a]D22 ꢀ11.6
(cꢂ0.97, MeOH)} in 95% yield. The melting point and the
optical rotation of the product were in good agreement with
those already reported (3R)-Piz {lit.14) mp 147—149 °C,
[a]D22 ꢀ12.0 (cꢂ1, MeOH)}. Similarly, 33 {mp 145—
147 °C, [a]D22 ꢃ11.6 (cꢂ0.97, MeOH)} was obtained from
the (S)-form 31 in 95% yield. Thus, the absolute configura-
tion of the levorotatory Piz 32 and its precursor Piz was as-
(6) The reaction was carried out in refluxing benzene for 60 h. Colorless
needles, mp 95—96 °C (from hexane). MS m/z 309 (Mꢃ). IR (KBr) cmꢀ1
:
2239 (CN), 1724, 1701 (CꢂO). 1H-NMR (CDCl3) d: 1.48 and 1.50 (total
9H, intensity ratio 3 : 4, each s, t-Bu), 1.51 (9H, s, t-Bu), 3.50—3.89 and
4.41—4.72 (2H, m, 6-H2), 5.19—5.57 (1H, br, 3-H), 5.63—5.93 (1H, br, 4-
H), 5.93—6.22 (1H, br, 5-H). 13C-NMR (CDCl3) d: 27.9 (q), 28.0 and 28.2
(each q), 42.1 (t), 43.0 (d), 81.6 and 82.3 (each s), 83.0 (s), 83.5 and 83.7
(each s), 115.3 (s), 119.3 and 119.6 (each d), 128.4 and 129.1 (each d),
152.9 (s), 153.6 and 154.2 (each s). Anal. Calcd for C15H23N3O4: C, 58.24;
H, 7.49; N, 13.58. Found: C, 58.04; H, 7.35; N, 13.82.
Di-tert-butyl 3-Methoxy-1,2,3,6-tetrahydropyridazine-1,2-dicarboxyl-
ate (7) The reaction was carried out in CH2Cl2 at room temperature for
2 h. Colorless oil. MS m/z 314 (Mꢃ). IR (neat) cmꢀ1: 1706 (CꢂO). 1H-NMR
(CDCl3) d: 1.49 and 1.50 (each 9H, s, t-Buꢁ2), 3.49 and 3.53 (total 3H, in-
tensity ratio 4 : 1, each s, OMe), 3.55—3.83, 4.31 and 4.49 (1H, m, total 1H,
intensity ratio 1 : 4, d, Jꢂ18.7 Hz and dd, Jꢂ18.0, 2.9 Hz, 6-H2), 5.25—5.66
(1H, br, 3-H), 5.77—6.15 (2H, m, 4-, 5-H). 13C-NMR (CDCl3) d: 28.26 (q),
28.34 (q), 41.7 and 43.6 (each t), 56.2 (q), 80.3 (d), 80.8 and 81.0 (each s),
signed the (S)-configuration {lit.16) mp 149—151 °C, [a]D22 81.6 (s), 123.8 and 124.3 (each d), 127.2 and 127.7 (each d), 154.5 (s), 154.9

52
Vol. 57, No. 1
Chart 7
Chart 8
Chart 9
(s). HR-MS m/z: 314.1842 (Calcd for C15H26N2O5: 314.1842).
Cyanation of 3-Methoxy-1,2,3,6-tetrahydropyridazine (7) TMSCN
(2.00 ml, 15 mmol) was added to a solution of 7 (3.14 g, 10 mmol) in CH2Cl2
the filtrate was evaporated in vacuo. The resulting residue was chro-
matographed on silica gel using AcOEt–hexane to give 9, 10 and 12.
Hydrogenation of 3-Cyano-1,2,3,6-tetrahydropyridazine (6) with 70%
(40 ml) at ꢀ40 °C under argon atmosphere. BF3·OEt or TiCl4 (5 mmol) in HClO4 A mixture of 6 (0.93 g, 3 mmol), 10% Pd–C (40 mg) or PtO2
CH2Cl2 (10 ml) was added to the reaction mixture. The mixture was stirred (90 mg) and 70% HClO4 (2 drops) in EtOH (8 ml) was shaken in H2 (1 atm
under the conditions for 5 h (TiCl4: 1 h). 2% NaHCO3 solution was added to pressure) at room temperature for 1 h. After removal of the catalyst,
the mixture, and the aqueous mixture was vigorously stirred at room temper-
ature for 1 h. The mixture was extracted with CHCl3 (100 mlꢁ3). The or- aqueous mixture was extracted with AcOEt (30 mlꢁ3). The combined or-
ganic layer was washed with water (200 ml), dried over anhydrous Na2SO4 ganic layer was washed with brine (20 mlꢁ2), dried over anhydrous Na2SO4
and evaporated in vacuo. The resulting residue was chromatographed on sil- and evaporated in vacuo. The resulting residue was chromatographed on sil-
NaHCO3 saturated aqueous solution (5 ml) was added to the mixture. The
ica gel using AcOEt–hexane to give 6.
BF3·OEt: 2.90 g, 94%.
TiCl4: 2.83 g, 92%.
ica gel using AcOEt–hexane to give 9 and 12.
Di-tert-butyl 3-Cyanohexahydropyridazine-1,2-dicarboxylate (9)
Coleorless prisms mp 104—105 °C (from hexane). MS m/z 311 (Mꢃ). IR
1
One-Pot Synthesis of 3-Cyano-1,2,3,6-tetrahydropyridazine (6) To a
solution of azodicarboxylate (4, 2.30 g, 10 mmol) in CH2Cl2 (10 ml) was (each 9H, s, t-Bu), 1.67—1.73 and 1.86—2.05 (1H, m , 3H, m, 5-H2, 4-H2),
added 1-methoxy-1,3-butadiene (3, 1.11 ml, 11 mmol) or 1-trimethoxysilyl- [2.82 and 2.87—3.11 (total 1H, intensity ratio 2 : 1, t, Jꢂ11.8 Hz, m), 3.94,
(KBr) cmꢀ1: 2241 CN), 1697 (CꢂO). H-NMR (CDCl3) d: 1.48 and 1.50
oxy-1,3-butadiene (8, 1.93 ml, 11 mmol) at room temperature. After stirring
4.10 and 4.28 (total 1H, intensity ratio 1 : 6 : 20, d, Jꢂ12.8 Hz, d, Jꢂ11.9 Hz,
d, Jꢂ13.5 Hz), 6-H2], 4.65—4.80, 5.20—5.22 and 5.22—5.40 (total 1H, in-
for 30 min, a solution of TMSCN (2.00 ml, 15 mmol) in CH2Cl2 (30 ml) and
then a solution of BF3·OEt (0.63 ml, 5 mmol) in CH2Cl2 (10 ml) were added tensity ratio 1 : 3 : 10, each br, 3-H). 13C-NMR (CDCl3) d: 20.1 (t), 27.1 (t),
to the stirring mixture at ꢀ40 °C under argon atmosphere. The mixture was 28.0 (q), 28.2 (q), 43.0 (t), 43.7 (d), 81.8 (s), 82.6 (s), 116.5 (s), 152.8 (s),
stirred under the conditions until disappearance of the starting material. 2%
NaHCO3 solution (100 ml) was added to the mixture, and the aqueous mix-
ture was vigorously stirred at room temperature for 1 h. The mixture was ex-
153.6 (s). Anal. Calcd for C15H25N3O4: C, 57.86; H, 8.09; N, 13.49. Found:
C, 58.01; H, 8.00; N, 13.36.
Di-tert-butyl 3-Cyano-1,2,5,6-tetrahydropyridazine-1,2-dicarboxylate
tracted with CHCl3 (100 mlꢁ3). The organic layer was washed with water (10) Colorless oil. MS m/z 209 [(MHꢀBoc)ꢃ], 109 [(MH2ꢀ2Boc)ꢃ]. IR
(200 ml), dried over anhydrous Na2SO4 and evaporated in vacuo. The result- (neat) cmꢀ1: 2231 (CN), 1720 (CꢂO). H-NMR (CDCl3) d: 1.48 and 1.55
ing residue was chromatographed on silica gel using AcOEt–hexane to give (total 18H, intensity ratio 9 : 11, each s, t-Bu), [2.17 and 2.21 (total 1H, in-
1
6.
tensity ratio 1 : 1, each dd, Jꢂ4.8, 4.8 Hz), 2.41—2.57 (1H, m) 5-H2], 2.98—
3.22 and 4.29—4.48 (each 1H, m, 6-H2), 6.04—6.18 (1H, dd, Jꢂ4.8, 4.8 Hz,
4-H). 13C-NMR (CDCl3) d: 22.7 (t), 28.0 (q), 28.1 (q), 41.5 (t), 82.3 (s),
91% yield from 3.
80% yield from 8.
Hydrogenation of 3-Cyano-1,2,3,6-tetrahydropyridazine (6) A mix- 84.8 (s), 113.9 (s), 115.1 (s), 128.0 (d), 150.7 (s), 154.0 (s). HR-MS m/z:
ture of 6 (0.93 g, 3 mmol) and 10% Pd–C (40 mg) or PtO2 (90 mg) in EtOH 209.1160 (Calcd for C10H15N3O2: 209.1164), 109.0642 (Calcd for C5H7N3:
(8 ml) was shaken in H2 (1 atm pressure) at room temperature for 1—10 h 109.0640).
(until disappearance of the starting material). After removal of the catalyst,
Di-tert-butyl 3-(tert-Butoxycarbonylaminomethyl)hexahydropyri-

January 2009
53
1
dazine-1,2-dicarboxylate (12) Colorless oil. MS m/z 415 (Mꢃ). IR (neat)
cmꢀ1: 3423 (NH), 1722, 1693 (CꢂO). 1H-NMR (CDCl3) d: 1.38—1.59 and
1.66—1.83 (28H, m and 3H, m, t-Buꢁ3, 4-H2, 5-H2), 2.77—3.48 (3H, m, 3-
H, 6-H2), 3.83—4.45 (2H, m, CH2NHBoc), 4.70—4.95, 4.95—5.47 and
5.47—5.85 (total 1H, intensity ratio 1 : 10 : 4, each br, NH). 13C-NMR
(CDCl3) d: 19.3 and 19.8 (each t), 23.9, 24.1 and 24.8 (each t), 28.2 (q),
28.3 (q), 28.4 (q), 39.6 and 40.1 (each t), 42.8 and 45.5 (each t), 52.5 and
54.4 (each d), 78.9 (s), 79.1 (s), 81.5 (s), 154.0 (s), 155.1 (s), 156.0 (s). HR-
MS m/z: 415.2628 (Calcd for C20H37N3O6: 415.2682).
(ꢀ) Hexahydropyridazine-3-carboxylic Acid Trifluoroacetic Acid (13)
A mixture of 9 (621 mg, 2 mmol) and 6 M HCl (20 ml) was refluxed for 24 h
under argon atmosphere, and then evaporated in vacuo. The residue was de-
salted by ion-exchange chromatography on a Dowex 1ꢁ4 (50—100 mesh,
CH3COOꢀ form) column with water. After addition of AcOH (1 ml) to the
eluent, the eluent was concentrated to dryness. 10% CF3COOH was added
to the obtained residue, and the mixture was evaporated in vacuo to give
the crude trifluoroacetate, which was recrystallized from EtOH–AcOEt.
White powder, 454 mg, 93% yield, mp 146—147 °C. MS (FAB) m/z 131
[(MHꢀTFA)ꢃ]. IR (KBr) cmꢀ1: 3292, 3080, 2970 (OH, NH), 1724, 1664
(CꢂO). 1H-NMR (D2O) d: 1.81—1.90, 1.90—1.95 and 2.07—2.16 (2H, m,
1H, m, 1H, m, 4-H2, 5-H2), 3.12—3.18 and 3.25—3.31 (each 1H, m, 6-H2),
3.92 (1H, dd, Jꢂ8.0, 4.3 Hz, 3-H), 13C-NMR (D2O) d: 20.1 (t), 25.1 (t), 45.7
(t), 56.6 (d), 117.1 (qF, 1JCFꢂ291.7 Hz), 163.7 (qF, 2JCFꢂ35.1 Hz), 174.6 (s).
Anal. Calcd for C17H11F3N2: C, 34.43; H, 4.54; N, 11.47. Found: C, 34.52;
H, 4.43; N, 11.27.
1696 (CꢂO). H-NMR (CDCl3) d: 1.49 and 1.52 (total 18H, intensity ratio
2 : 3, each s, t-Buꢁ2), 2.01 and 2.16 (1H, ddd, Jꢂ14.4, 6.6, 3.0 Hz and 1H,
dd, Jꢂ14.4, 1.4 Hz, 4-H2), 2.58—2.82 and 2.82—2.98 (total 1H, intensity
ratio 2 : 9, each br, OH), 3.02, 3.08—3.39 and 4.34 (total 2H, intensity ratio
5 : 2 : 7, d, Jꢂ14.2 Hz, m, d, Jꢂ14.2 Hz, 6-H2), 4.03—4.22 (1H, m, 5-H),
5.03—5.09 and 5.27—5.30 (total 1H, intensity ratio 2 : 7, each m, 3-H). 13C-
NMR (CDCl3) d: 27.9 (q), 28.2 (q), 32.6 (t), 39.0 and 41.2 (each d), 49.4 (t),
62.1 (d), 82.4 (s), 82.7 (s), 117.4 (s), 152.7 (s), 155.2 (s). Anal. Calcd for
C15H25N3O5: C, 55.03; H, 7.70; N, 12.84. Found: C, 55.10; H, 7.52; N,
12.78.
Di-tert-butyl trans-3-Cyano-5-hydroxyhexahydropyridazine-1,2-dicar-
boxylate (19) Colorless prisms, mp 103—105 °C (from benzene–hexane).
MS (FAB) m/z 328 (MHꢃ). IR (KBr) cmꢀ1: 3498 (OH), 2249 (CN), 1718,
1
1687 (CꢂO). H-NMR (CDCl3) d: 1.48 and 1.49 (total 18H, intensity ratio
5 : 1, each s, t-Buꢁ2), 1.78, 2.23 and 2.27—2.44 (total 2H, intensity ratio
4 : 3 : 1, ddd, Jꢂ16.7, 13.1, 5.7 Hz, ddd, Jꢂ13.3, 2.1, 2.1 Hz, m, 4-H2), [2.60,
2.66—2.79 (total 1H, intensity ratio 2 : 1, dd, Jꢂ11.7, 11.2 Hz, m), 4.22 and
4.38 (total 1H, intensity ratio 1 : 5, dd, Jꢂ12.6, 4.6 Hz and dd, Jꢂ13.1,
4.4 Hz), 6-H2], 3.17—3.29 and 3.49—3.66 (total 1H, intensity ratio 1 : 7,
each br, OH), 4.04—4.15 (1H, m, 5-H), 5.21—5.30 and 5.30—5.48 (total
1H, intensity ratio 1 : 3, each br, 3-H). 13C-NMR (CDCl3) d: 28.0 (q), 28.1
(q), 35.1 and 35.7 (each t), 43.6 and 45.2 (each d), 49.6 and 51.2 (each t),
62.0 (s), 82.5 (s), 83.2 (s), 116.4 (s), 152.6 (s), 153.8 (s). Anal. Calcd for
C15H25N3O5: C, 55.03; H, 7.70; N, 12.84. Found: C, 54.98; H, 7.51; N,
12.74.
cis-1-(2,4-Dinitrophenyl)-5-hydroxyhexahydropyridazine-3-carboxylic
Acid (22) A solution of cis-18 (981 mg, 3 mmol) in AcOH (30 ml) and 6 M
HCl (30 ml) was heated at 120 °C (bath temp.) for 24 h and then evaporated
in vacuo. The obtained residue was dissolved in water (15 ml). Saturated
NaHCO3 aqueous solution (15 ml) and a solution of 1-fluoro-2,4-dinitroben-
zene (1.15 ml, 9 mmol) in EtOH (25 ml) were added to the aqueous mixture
at 0 °C, the whole mixture (pH 7—8) was stirred at room temperature for
2 h. After addition of 1% NaHCO3 aqueous solution (45 ml) at 0 °C, the
mixture was washed with ether (50 mlꢁ2), acidified with 2 M HCl (pH 3),
and then extracted with ether (50 mlꢁ3). The organic layer was washed with
brine (100 mlꢁ4), dried over Na2SO4, and concentrated in vacuo. The
residue was chromatographed on silica gel using ether–MeOH to give 22.
Yellow prisms, mp 200 °C (decomp., from EtOH–ether–hexane), 92% yield.
MS m/z 312 (Mꢃ). IR (KBr) cmꢀ1: 3392 (OH, NH), 1733, 1610 (CꢂO). 1H-
NMR (DMSO-d6) d: 1.32 (1H, ddd, Jꢂ12.0, 11.9, 11.0 Hz, 4-Hax), 2.20
(1H, ddd, Jꢂ12.0, 3.5, 3.2 Hz, 4-Heq), 2.80 (1H, dd, Jꢂ11.0, 11.0 Hz, 6-
Hax), 3.34 (1H, ddd, J ꢂ 11.9, 11.9, 3.0 Hz, 3-H), 3.71—3.80 (1H, m, 5-H),
3.98 (1H, dd, Jꢂ11.8, 4.8 Hz, 6-Heq), 5.09 (1H, d, Jꢂ11.9 Hz, NH), 5.20—
5.45 (1H, br, OH), 7.22 (1H, d, Jꢂ9.4 Hz, 6ꢄ-H in Ph-H), 8.19 (1H, ddd,
Jꢂ9.4, 2.7, 0.5 Hz, 5ꢄ-H in Ph-H), 8.33 (1H, dd, Jꢂ2.7, 0.5 Hz, 3ꢄ-H in Ph-
H), 12.54—13.20 (1H, br, COOH). 13C-NMR (DMSO-d6) d: 36.9 (t), 52.5
(t), 56.0 (d), 63.7 (d), 115.2 (d), 121.7 (d), 127.2 (d), 136.4 (s), 137.5 (s),
147.1 (s), 171.8 (s). Anal. Calcd for C11H12N4O7: C, 42.31; H, 3.87; N,
17.94. Found: C, 42.32; H, 3.92; N, 17.87.
trans-1-(2,4-Dinitrophenyl)-5-hydroxyhexahydropyridazine-3-car-
boxylic Acid (23) The title compound was prepared from 19 in a similar
manner to that described for 22. Yellow powder, mp 164—165 °C (from
EtOH–ether–hexane), 72% yield. MS m/z 312 (Mꢃ). IR (KBr) cmꢀ1: 3415
(OH, NH), 1720, 1608 (CꢂO). 1H-NMR (DMSO-d6) d: 1.70 (1H, dd,
Jꢂ11.5, 10.8 Hz, 4-Hax), 1.87 (1H, ddd, Jꢂ13.1, 3.1, 3.1 Hz, 4-Heq), 3.38
and 3.77—3.83 (each 1H, d, Jꢂ12.4 Hz, br, 6-H2), 3.73 (1H, ddd, Jꢂ11.2,
11.1, 3.0 Hz, 3-H), 4.05—5.14 (1H, m, 5-H), 5.09—5.14 (1H, br, OH), 5.18
(1H, d, Jꢂ11.2 Hz, NH), 7.18 (1H, d, Jꢂ9.4 Hz, 6ꢄ-H in Ph-H), 8.15 (1H,
dd, Jꢂ9.4, 2.5 Hz, 5ꢄ-H in Ph-H), 8.30 (1H, d, Jꢂ2.5 Hz, 3ꢄ-H in Ph-H),
12.24—12.95 (1H, br, COOH). 13C-NMR (DMSO-d6) d: 34.0 (t), 60.2 (t),
61.8 (d), 72.2 (d), 115.1 (d), 121.8 (d), 126.9 (d), 135.4 (s), 136.8 (s), 148.1
(s), 172.7 (s). Anal. Calcd for C11H12N4O7: C, 42.31; H, 3.87; N, 17.94.
Found: C, 42.63; H, 3.97; N, 17.65.
Di-tert-butyl 3-Cyano-5-oxohexahydropyridazine-1,2-dicarboxylate
(17) To a solution of azodicarboxylate (4, 2.30 g, 10 mmol) in CH2Cl2
(10 ml) was added 1-methoxy-3-(trimethylsilyloxy)-1,3-butadiene (14, 90%,
2.38 ml, 11 mmol) at room temperature, and the mixture was stirred for
30 min. A solution of TMSCN (2.00 ml, 15 mmol) in CH2Cl2 (30 ml) and
then a solution of BF3·OEt (0.63 ml, 5 mmol) in CH2Cl2 (10 ml) were added
to the stirring mixture at ꢀ40 °C under argon atmosphere. The mixture was
stirred under the conditions for 24 h. 2% NaHCO3 aqueous solution (100 ml)
was added to the mixture, and the aqueous mixture was vigorously stirred
at room temperature for 1 h. The mixture was extracted with CHCl3
(100 mlꢁ3). The organic layer was washed with water (200 ml), dried over
anhydrous Na2SO4 and evaporated in vacuo. The resulting residue was chro-
matographed on silica gel using CHCl3–MeOH (100 : 1) to give 17 (3.06 g,
94% yield). Colorless needles, mp 129—130 °C (from benzene–hexane).
MS (FAB) m/z 326 (MHꢃ). IR (KBr) cmꢀ1: 2247 (CN), 1747, 1723 (CꢂO).
1H-NMR (CDCl3) d: 1.50, 1.51 and 1.55 (total 18H, intensity ratio 1 : 2 : 7,
each s, t-Buꢁ2), 2.84—2.98 (2H, m, 4-H2), 3.57—4.04, 4.45—4.62 and
4.74 (total 2H, intensity ratio 10 : 3 : 7, m, br, d, Jꢂ18.1 Hz, 6-H2), 4.98—
5.23 and 5.23—5.53 (total 1H, intensity ratio 3 : 7, m, 3-H). 13C-NMR
(CDCl3) d: 27.8 and 28.0 (each q), 28.1 (q), 39.9 and 40.1 (each t), 43.9 and
45.8 (each d), 55.8 and 56.0 (each t), 83.5 (s), 84.0 (s), 116.3 (s), 152.2 (s),
153.4 (s), 199.4 (s). Anal. Calcd for C15H23N3O5: C, 55.37; H, 7.13; N,
12.91. Found: C, 55.51; H, 7.00; N, 13.07.
NaBH4 Reduction of 3-Cyano-5-oxohexahydropyridazine (17) NaBH4
(567 mg, 15 mmol) was added to a stirred solution of 17 (3.25 g, 10 mmol)
in EtOH (150 ml) at ꢀ0 °C, and the reaction mixture was stirred until dis-
appearance of the starting material. Cold water (10 ml) was added to the
mixture, the aqueous mixture was acidified with AcOH (the range of the pH
value: 5—6). The whole mixture was evaporated, and water (100 ml) was
added to the residue. The obtained aqueous mixture was extracted with
AcOEt (300 mlꢁ3). The combined organic layer was washed with water
(200 ml), dried over anhydrous Na2SO4 and evaporated in vacuo. The result-
ing residue was chromatographed on silica gel using AcOEt–hexane to give
18 and 19.
LiAl(Ot-Bu)3H Reduction of 3-Cyano-5-oxohexahydropyridazine (17)
A solution of 17 (3.25 g, 10 mmol) in dry THF (70 ml) was slowly added to
a stirred solution of LiAl(Ot-Bu)3H (5.09 g, 20 mmol) in THF (80 ml) at
ꢀ20 °C under argon atmosphere, and the mixture was stirred for 3 h under
the same conditions. An aqueous solution of NH4Cl (1.75 g) in water (20 ml)
was slowly added to the mixture, and the aqueous mixture was acidified with
2 M HCl (the range of the pH value: 5—6). The obtained precipitate was fil-
tered off, well washed with THF (100 ml). The filtrate was concentrated and
extracted with AcOEt (300 mlꢁ3). The combined organic layers were
washed with water (200 ml), dried over anhydrous Na2SO4 and evaporated in
vacuo. The resulting residue was chromatographed on silica gel using
AcOEt–hexane to give 18 and 19.
Di-tert-butyl trans-5-Chloro-3-cyanohexahydropyridazine-1,2-dicar-
boxylate (24) A mixture of 18 (0.57 g, 1.73 mmol), CCl4 (2.6 ml) and PPh3
(0.76 g, 2.86 mmol) in dry THF (2.6 ml) was stirred at 20 °C under argon
atmosphere for 3 d, and then evaporated in vacuo. The residue was treated
with a mixed solvent of AcOEt, CHCl3 and hexane (5, 21, 14 ml). After fil-
tration off for removal of the precipitate (Ph3PO), the obtained filtrate was
concentrated in vacuo. The residue was chromatographed on silica gel using
hexane–AcOEt to give 24. Colorless prisms, mp 119—120 °C (from
hexane), 70% yield. MS m/z 345, 347 (Mꢃ). IR (KBr) cmꢀ1: 2256 (CN),
Di-tert-butyl cis-3-Cyano-5-hydroxyhexahydropyridazine-1,2-dicar-
boxylate (18) Colorless plates, mp 160—162 °C (from benzene–hexane).
MS (FAB) m/z 328 (MHꢃ). IR (KBr) cmꢀ1: 3491 (OH), 2242 (CN), 1721,
1
1712 (CꢂO). H-NMR (CDCl3) d: 1.49, 1.50 and 1.51 (total 18H, each s,
intensity ratio 4 : 7 : 1, t-Buꢁ2), 2.06 and 2.46 (each 1H, ddd, Jꢂ13.5, 12.0,

54
Vol. 57, No. 1
described for 13. White powder, mp 145—147 °C (from EtOH–AcOEt)
(lit.16) mp 149—151 °C), 91%. IR (KBr) cmꢀ1: 3442, 3292, 3080 (OH, NH),
1720, 1664 (CꢂO). [a]D28 ꢃ11.6 (cꢂ1.03, MeOH).
5.5 Hz and ddd, Jꢂ13.5, 2.1, 2.1 Hz, 4-H2), 2.74—3.09, 4.32—4.44 and 4.60
(total 2H, intensity ratio 6 : 1 : 5, m, m and dd, Jꢂ13.3, 3.9 Hz, 6-H2), 4.13—
4.27 (1H, m, 5-H), 5.11—5.30 and 5.30—5.54 (total 1H, intensity ratio 3 : 7,
each br, 3-H). 13C-NMR (CDCl3) d: 27.9 (q), 28.1 (q), 36.9 (t), 44.2 (d),
48.3 (t), 49.8 (d), 82.8 (s), 83.4 (s), 116.7 (s), 152.3 (s), 152.9 (s). Anal.
Calcd for C15H24ClN3O4: C, 52.10; H, 7.00; N, 12.15. Found: C, 52.27; H,
6.95; N, 12.21.
Acknowledgements This work was partially supported by The Specific
Research Fund of Hokuriku University.
References
Di-tert-butyl cis-5-Chloro-3-cyanohexahydropyridazine-1,2-dicar-
boxylate (25) The title compound was prepared from 19 in a similar man-
ner to that described for 24. Colorless prisms, mp 129—130 °C (from ben-
zene–hexane), 60% yield. MS m/z 345, 347 (Mꢃ). IR (KBr) cmꢀ1: 2245
(CN), 1728, 1705 (CꢂO). 1H-NMR (CDCl3) d: 1.49, 1.53 and 1.54 (total
18H, intensity ratio 3 : 3 : 4, each s, t-Buꢁ2), 2.30—2.34 (2H, m, 4-H2),
3.20—3.54, 4.35 and 4.54 (total 2H, intensity ratio 5 : 1 : 4, m, d, Jꢂ14.2 Hz
and dd, Jꢂ14.4, 1.8 Hz, 6-H2), 4.24—4.32 (1H, m, 5-H), 5.05—5.25 and
5.25—5.43 (total 1H, intensity ratio 4 : 1, each br, 3-H). 13C-NMR (CDCl3)
d: 27.9 (q), 28.1 and 28.2 (each q), 33.6 and 33.8 (each t), 38.7 (d), 49.3 (t),
50.7 and 50.9 (each d), 82.5 (s), 83.2 (s), 116.6 (s), 152.5 (s), 152.7 (s).
Anal. Calcd for C15H24ClN3O4: C, 52.10; H, 7.00; N, 12.15. Found: C,
52.04; H, 6.75; N, 12.12.
trans-5-Chloro-1-(2,4-dinitrophenyl)hexahydropyridazine-3-car-
boxylic Acid (27) The title compound was prepared from 24 in a similar
manner to that described for 22. Yellow prisms, mp 186—189 °C (decomp.,
from EtOH–ether–hexane), 81% yield. MS m/z 330, 332 (Mꢃ). IR (KBr)
cmꢀ1: 3263 (OH, NH), 1736, 1608 (CꢂO). 1H-NMR (DMSO-d6) d: 1.98—
2.19 (2H, m, 4-H2), 3.55—3.75, 3.95—4.22 (each 1H, br, 6-H2), 3.80 (1H,
ddd, Jꢂ11.0, 11.0, 3.5 Hz, 3-H), 4.84 (1H, br, 5-H), 5.39 (1H, d, Jꢂ11.1 Hz,
NH), 7.24 (1H, d, Jꢂ9.5 Hz, 6ꢄ-H in Ph-H), 8.19 (1H, dd, Jꢂ9.5, 2.7 Hz, 5ꢄ-
H in Ph-H), 8.36 (1H, d, Jꢂ2.7 Hz, 3ꢄ-H in Ph-H), 12.9 (1H, br s, COOH).
13C-NMR (DMSO-d6) d: 34.7 (t), 51.9 (t), 52.4 (d), 55.0 (d), 115.1 (d),
121.8 (d), 127.2 (d), 136.6 (s), 137.4 (s), 147.5 (s), 171.8 (s). Anal. Calcd for
C11H11ClN4O6: C, 39.95; H, 3.35; N, 16.94. Found: C, 40.07; H, 3.47; N,
16.79.
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Di-(ꢁ)-menthyl 3-Cyano-1,2,3,6-tetrahydropyridazine-1,2-dicarboxyl-
ate (29) The title compound was prepared as a mixture of the diastere-
omers from 3 and menthyl carboxylate (28)28) in a similar manner to that de-
scribed for 6. Colorless oil, 99% yield. MS m/z 473 (Mꢃ). IR (neat) cmꢀ1
:
2245 (CN), 1713 (CꢂO). 1H-NMR (CDCl3) d: 0.67—1.15 (24H, m, 2ꢄ-iso-
propyl-Hꢁ2, 5ꢄ-Meꢁ2, 4ꢄ-H2ꢁ2), 1.29—1.57 (4H, br, 3ꢄ-H2ꢁ2), 1.62—
2.21 (8H, m, 2ꢄ-Hꢁ2, 5ꢄ-Hꢁ2, 6ꢄ-H2ꢁ2), 3.61—4.00 and 4.35—4.82 (1H,
m, 3H, m, 6-H2ꢁ2, 1ꢄ-Hꢁ2), 5.27—5.73 (1H, br, 3-H), 5.85 (1H, br s, 4-H),
6.11 (1H, br s, 5-H).
Hydrogenation of 29 with 70% HClO4 Compound 29 was hydro-
genated in EtOH and worked up as described for 9 to give 30 and 31.
Di-(ꢁ)-menthyl (3R)-3-Cyanohexahydropyridazine-1,2-dicarboxylate
(30) Colorless prisms, mp 108—109 °C (from hexane). MS (FAB) m/z 476
(MHꢃ). IR (KBr) cmꢀ1: 2251 (CN), 1716 (CꢂO). 1H-NMR (CDCl3) d:
0.67—1.15 (24H, m, 2ꢄ-isopropyl-Hꢁ2, 5ꢄ-Meꢁ2, 4ꢄ-H2ꢁ2), 1.23—1.56
(4H, m, 3ꢄ-H2ꢁ2), 1.60—2.20 (12H, m, 2ꢄ-Hꢁ2, 5ꢄ-Hꢁ2, 6ꢄ-H2ꢁ2, 4-H2,
5-H2), [2.73—3.08 (1H, m), 4.19 and 4.34 (total 1H, intensity ratio 1 : 4,
each d, Jꢂ13.5 and 11.7 Hz), 6-H2], 4.50—4.76 (2H, m, 1ꢄ-Hꢁ2), 5.13—
5.48 (1H, br, 3-H). [a]D25 ꢀ26.8 (cꢂ0.95, CHCl3). Anal. Calcd for
C27H45N3O4: C, 68.18; H, 9.54; N, 8.83. Found: C, 68.12; H, 9.34; N, 8.81.
Di-(ꢁ)-menthyl (3S)-3-Cyanohexahydropyridazine-1,2-dicarboxylate
(31) Colorless prisms, mp 50—51 °C (from hexane). MS (FAB) m/z 476
1
(MHꢃ). IR (KBr) cmꢀ1: 2249 (CN), 1732, 1709 (CꢂO). H-NMR (CDCl3)
22) Mitsunobu O., Synthesis, 1981, 1—27 (1981).
23) Schmidt U., Braun C., Sutoris H., Synthesis, 1996, 223—229 (1996).
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2995—2998 (1998).
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25, 221—236 (1960) [Chem. Abstr., 54, 6719i (1960)].
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2370—2374 (1974) [Chem. Abstr., 82, 155249 (1997)].
27) Starr J. T., Rai G. S., Dang S. R., Dang H., Mcnelis B. J., Synth. Com-
mun., 27, 3197—3200 (1997).
d: 0.70—1.15 (24H, m, 2ꢄ-isopropyl-Hꢁ2, 5ꢄ-Meꢁ2, 4ꢄ-H2ꢁ2), 1.30—1.57
(4H, m, 3ꢄ-H2ꢁ2), 1.62—2.19 (12H, m, 2ꢄ-Hꢁ2, 5ꢄ-Hꢁ2, 6ꢄ-H2ꢁ2, 4-H2,
5-H2), [2.75—3.18 (1H, m), 4.17 and 4.33 (total 1H, intensity ratio 2 : 3,
each d, Jꢂ12.8 and 11.5 Hz), 6-H2], 4.50—4.77 (2H, m, 1ꢄ-Hꢁ2), 5.12—
5.44 (1H, br, 3-H). [a]D25 ꢀ82.9 (cꢂ0.97, CHCl3). Anal. Calcd for
C27H45N3O4: C, 68.18; H, 9.54; N, 8.83. Found: C, 67.99; H, 9.23; N, 8.67.
(3R)-Hexahydropyridazine-3-carboxylic Acid Trifluoroacetic Acid
(32) The title compound was prepared from 30 in a similar manner to that
described for 13. White powder, mp 145—147 °C (from EtOH–AcOEt)
(lit.14) mp 147—149 °C), 95% yield. IR (KBr) cmꢀ1: 3442, 3292, 3080 (OH,
NH), 1720, 1664 (CꢂO). [a]D22 ꢀ11.6 (cꢂ0.97, MeOH).
28) Brimble M. A., Heathcock C. H., Nobin G. N., Tetrahedron Asymme-
try, 7, 2007—2016 (1996).
(3S)-Hexahydropyridazine-3-carboxylic Acid Trifluoroacetic Acid
(33) The title compound was prepared from 31 in a similar manner to that